Heteroazabenzobicyclic carboxamide 5-HT3 antagonists

ABSTRACT

This invention relates to heteroazabenzo-bicyclic substituted carboxamide compounds of the formula: ##STR1## where W is O, S or NR 5  and 
     Z is ##STR2## 3-quinuclidine, 4-quinuclidine, 
     4-(1-azabicyclo[3.3.1]nonane), 
     3-(9-methylazabicyclo[3.3.1]nonane), 
     7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or 
     4-[3-methoxy-1-(3-[4-fluorophenoxy[propyl)piperidine]; 
     which exhibit 5-HT 3  antagonist properties including CNS, anti-emetic and gastric prokinetic activity. This invention further relates to pharmaceutical compositions and methods for the treatment of the above disorders.

FIELD OF THE INVENTION

This invention relates to heteroazabenzobicyclic substituted carboxamidecompounds which exhibit 5-HT₃ antagonist properties including CNS,anti-emetic and gastric prokinetic activity and which are void of anysignificant D₂ receptor binding affinity. This invention also relates topharmaceutical compositions and methods for the treatment ofgastrointestinal and mental disorders using said compounds.

5-Hydroxytryptamine, abbreviated "5-HT", is commonly known as serotonin.Serotonin is found throughout the body including the gastrointestinaltract, platelets, spleen and brain, appears to be involved in a greatnumber of physiological processes such as neurotransmission at certainneurones in the brain, and is implicated in a number of central nervoussystem (CNS) disorders. Additionally, serotonin appears to act as alocal hormone in the periphery; it is released in the gastrointestinaltract, where it increases small intestinal motility, inhibits stomachand colon motility, and stimulates stomach acid production. Serotonin ismost likely involved in normal intestinal peristalsis.

The various physiological activities exerted by serotonin are related tothe variety of different receptors found on the surface membrane ofcells in different body tissue. The first classification of serotoninreceptors included two pharmacologically distinct receptors discoveredin the guinea pig ileum. The "D" receptor mediates smooth musclecontraction and the "M" receptor involves the depolarization ofcholinergic nerves and release of acetylcholine. Three different groupsof serotonin receptors have been identified and the following assignmentof receptors has been proposed: D-receptors are 5-HT₂ -receptors;M-receptors are termed 5-HT₃ -receptors; and all other receptors, whichare clearly not 5-HT₂ or 5-HT₃, should be referred to as 5-HT₁ -like.

5-HT₃ -receptors have been located in non-neurological tissue, braintissue, and a number of peripheral tissues related to differentresponses. It has been reported that 5-HT₃ -receptors are located onperipheral neurones where they are related to serotonin's (excitatory)depolarizing action. The following subtypes of 5-HT₃ receptor activityhave been reported: action involving postganglionic sympathetic andparasympathetic neurones, leading to depolarization and release ofnoradrenaline and acetylcholine, respectively (5-HT_(3B) subtype);action on enteric neurones, where serotonin may modulate the level ofacetylcholine (5-HT_(3C) subtype); and action on sensory nerves such asthose involved in the stimulation of heart nerve endings to produce areflex bradycardia (5-HT_(3A) subtype), and also in the perception ofpain.

Highly selective 5-HT₃ -antagonists have been shown to be very effectiveat controlling and preventing emesis (vomiting) induced by chemotherapyand radiotherapy in cancer patients. The anti-emetic effects of 5-HT₃-antagonists in animals exposed to cancer chemotherapy or radiation aresimilar to those seen following abdominal vagotomy. The antagonistcompounds are believed to act by blocking 5-HT₃ -receptors situated onthe cell membranes of the tissue forming the vagal afferent input to theemetic coordinating areas on the brain stem.

Serotonin is also believed to be involved in the disorder known asmigraine headache. Serotonin released locally within the blood vesselsof the head is believed to interact with elements of the perivascularneural plexus of which the afferent, substance P-containing fibers ofthe trigeminal system are believed relevant to the condition. Byactivating specific sites on sensory neuronal terminals, serotonin isbelieved to generate pain directly and also indirectly by enhancing thenociceptive effects of other inflammatory mediators, for examplebradykinin. A further consequence of stimulating the afferent neuroneswould be the local release of substance P and possibly other sensorymediators, either directly or through an axon reflex mechanism, thusproviding a further contribution to the vascular changes and pain ofmigraine. Serotonin is known to cause pain when applied to the exposedblister base or after an intradermal injection; and it also greatlyenhances the pain response to bradykinin. In both cases, the painmessage is believed to involve specific 5-HT₃ receptors on the primaryafferent neurones.

5-HT₃ -antagonists are also reported to exert potential antipsychoticeffects, and are believed to be involved in anxiety. Although notunderstood well, the effect is believed to be related to the indirectblocking of serotonin 5-HT₃ -mediated modulation of dopamine activity.

Many workers are investigating various compounds having 5-HT₃-antagonist activity.

Reported Developments

The development of 5-HT₃ agents originated from work carried out withmetoclopramide (Beecham's Maxolon, A. H. Robins' Reglan), which ismarketed for use in the treatment of nausea and vomiting at high doses.Metoclopramide is a dopamine antagonist with weak 5-HT₃ -antagonistactivity, which becomes more prominent at higher doses. It is reportedthat the 5-HT₃ activity and not the dopamine antagonism is primarilyresponsible for its anti-emetic properties. Other workers areinvestigating this compound in connection with the pain and vomitingaccompanying migraine.

Merrell Dow's compound MDL-72222 is reported to be effective as an acutetherapy for migraine, but toxicity problems have reportedly ended workon this compound. Currently four compounds, A. H. Robins' Zacopride,Beecham's BRL-43694, Glaxo's GR-38032F and Sandoz' ICS-205-930 are inclinical trials for use in chemotherapy-induced nausea and vomiting.GR-38032F is also in clinical trials in anxiety and schizophrenia, andreportedly, Zacopride in anxiety, while ICS-205-930 has been shown to beuseful in treating carcinoid syndrome.

Compounds reported as gastroprokinetic agents include Beecham'sBRL-24924, which is a serotonin-active agent for use in gut motilitydisorders such as gastric paresis, audition reflux esophagitis, and isknow to have also 5-HT₃ -antagonist activity.

Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized bya carboxamide moiety situated para to the amino group of2-chloro-4-methoxy aniline. BRL-43694, ICS-205930, GR-38032F andGR-65630 are characterized by a carbonyl group in the 3-position ofindole or N-methyl indole. MDL-72222 is a bridged azabicyclic3,5-dichlorobenzoate, while Zacopride, BRL-24924, BRL-43694 andICS-205930 have also bridged azabicyclic groups in the form of acarboxamide or carboxylic ester.

Bicyclic oxygen containing carboxamide compounds wherein the carboxamideis ortho to the cyclic oxygen moiety are reported to have antiemetic andantipsychotic properties in EPO Publ. No. 0234872.

Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines arereported to have 5HT₃ -antagonist and gastroprokinetic activity incopending application Ser. Nos. 152,112, 152,192, and 168,824 all ofwhich are assigned to the same assignee as the present application.

SUMMARY OF THE INVENTION

This invention relates to bicyclic benzoheteroazacyclic carboxamidecompounds having 5-HT₃ antagonist activity, gastric prokinetic,anti-emetic activity and lack P₂ receptor binding activity. Preferredcompounds of this invention are of the formula ##STR3## wherein: W is O,S or N--R₅ ;

X is hydrogen, alkyl alkoxy, hydroxy, amino, mono- and di-alkylamino,halo, trifluoromethyl, nitro, sulfamyl, mono- and di-alkylsulfamyl,alkylsulfonyl, carboxy, carbalkoxy, carbamyl or mono- anddi-alkylcarbamyl;

Y is hydrogen, alkyl, alkenyl, aralkyl, ##STR4## Z is ##STR5##3-quinuclidine, 4-quinuclidine, 4-(1-azabicyclo[3.3.1]nonane),3-(9-methylazabicyclo[3.3.1]-nonane),7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine];

R and R₅ are independently hydrogen, alkyl, formyl or acetyl;

R₁, R₂, R₃ and R₄ are independently hydrogen or alkyl;

vicinal R₂ groups may together form a carbocyclic ring;

vicinal R₁ groups may form a double bond;

vicinal R and R₁ groups may form a double bond when m is 3;

a and b are 1 to 4;

m is 1 to 3;

n is 0 to 2;

m+n is 1 to 3;

and pharmaceutically acceptable salts thereof.

This invention relates also to pharmaceutical compositions including aneffective therapeutic amount of the aforementioned bicyclicbenzoheteroazacyclic carboxamide compound and therapeutic methods forthe treatment of a patient suffering from gastrointestinal and/orpsychochemical imbalances in the brain by administering saidpharmaceutical composition.

Another aspect of the present invention relates to a process for thepreparation of the above-described compounds.

DETAILED DESCRIPTION

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight or branched-chained containing from about 1 to about 6 carbonatoms.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms.

"Aralkyl" means an alkyl group substituted by an aryl radical where arylmeans a phenyl or phenyl substituted with one or more substituents whichmay be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkyl mercaptyl,carboalkyl or carbamoyl. The preferred aralkyl groups are benzyl orphenethyl.

"Carbamyl" means a group of the formula ##STR6##

"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previouslydescribed. Lower alkoxy groups are preferred. Exemplary groups includemethoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Acyl" means an organic radical derived from an organic acid, acarboxylic acid, by the removal of its acid hydroxyl group. Preferredacyl groups are benzoyl and lower alkyl carboxylic acids groups such asacetyl and propionyl.

The chemical structures for the Z groups defined above are presentedbelow. ##STR7##

Certain of the compounds of the present invention may exist in enolic ortautomeric forms, and all of these forms are considered to be includedwithin the scope of this invention.

The compounds of this invention may be useful in the form of the freebase, in the form of salts and as a hydrate. All forms are within thescope of the invention. Acid addition salts may be formed and are simplya more convenient form for use; and in practice, use of the salt forminherently amounts to use of the base form. The acids which can be usedto prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound are preferred, all acid addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification and identification, or whenit is used as an intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures. Pharmaceutically acceptable saltswithin the scope of the invention are those derived from the followingacids: mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid and sulfamic acid; and organic acids such as aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and thelike. The corresponding acid addition salts comprise the following:hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate,tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid addition salts of the compounds of this invention are preparedeither by dissolving the free base in aqueous or aqueous-alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution.

A preferred class of compounds is described by Formula I: ##STR8##where: W is O, S or N-R₅ ;

X is hydrogen, hydroxy, amino, mono- and di-loweralkylamino, halo,trifluoromethyl, sulfamyl, mono- and di-loweralkylsulfamyl orloweralkylsulfonyl;

Y is loweralkyl, ##STR9## Z is ##STR10## 3-quinuclidine, 4-quinuclidine,4-(1-azabicyclo[3.3.1]nonane), 3-(9-methylazabicyclo[3.3.1]-nonane),7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine];

R, R₁, R₂, R₃, R₄ and R₅ are independently hydrogen or loweralkyl;

vicinal R₂ groups may together form a carbocyclic ring;

vicinal R₁ groups may form a double bond;

vicinal R and R₁ groups may form a double bond when m is 3;

a and b are 1 to 3;

m is 1 to 3;

n is 0 to 2;

m+n is 1 to 3;

and pharmaceutically acceptable salts thereof.

More preferred compounds are those of Formula II: ##STR11## where: W isO, S or N--R₅ ;

X is hydrogen or halo;

Y is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl,t-butyl, pentyl, ##STR12## Z is 3-quinuclidine, 4-quinuclidine,4-(1-azabicyclo[3.3.1]-nonane), 3-(9-methylazabicyclo[3.3.1]-nonane),7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine];

R, R₁, R₂ and R₅ are independently hydrogen, methyl or ethyl;

vicinal R₂ groups may together form a carbocyclic ring;

vicinal R₁ groups may form a double bond;

a is 1 to 3;

m is 1 or 2;

and pharmaceutically acceptable salts thereof.

The most preferred compounds are those of Formula III: ##STR13## where:W is oxygen or nitrogen;

X is chloro or bromo;

Y is methyl;

Z is 3-quinuclidine; 4-quinuclidine; or 4-[1-azabicyclo[3.3.1]nonane;

R is hydrogen or methyl;

R₁ and R₂ are independently hydrogen, methyl or ethyl;

vicinal R₂ groups may together form a carbocyclic ring;

vicinal R₁ groups may form a double bond; and pharmaceuticallyacceptable salts thereof.

Compounds of this invention may be prepared by the reaction of asuitable substituted carboxylic acid, acid halide or carboxylic ester ofa benzoxazole, benzothiazole, benzodiazole, benzoxazine, benzothiazine,benzodiazine, benzoxazepine, benzothiazepine, benzodiazepine, or dihydroor tetrahydro forms thereof, with an amine of the formula H₂ N-Zyielding the corresponding carboxamide. The reaction may be conducted attemperatures on the order of 0° C. using a stoichiometric amount ofethyl chloroformate in chloroform in the presence of triethylamine. Thechloroformate adduct is reacted with the amine of the formula H₂ N-Z toobtain the desired carboxamide. The reaction may also be conducted inthe presence of a dehydrating catalyst such as a carbodiimide in asolvent at room temperature.

The carboxylic acid starting compounds and derivatives thereof for theabove-mentioned reaction are also novel compounds and comprise part ofthe present invention. These materials comprise the appropriatelysubstituted benzoxazole, benzothiazole, benzodiazole, benzoxazine,benzothiazine, benzodiazine, benzoxazepine, benzothiazepine andbenzodiazepine compounds used to prepare the compounds of Formula I.More specifically, these intermediates comprise the appropriatelysubstituted saturated, partly saturated and unsaturated species of1,3-benzoxazole, 1,3-benzothiazole, 1,3,1(H)-benzodiazole,1,4,2(H)-benzoxazine, 3,1,4(H)-benzoxazine, 1,4,2(H)-benzothiazine,3,1,4(H)benzothiazine, 1,4-benzodiazine, 1,3-benzodiazine,1,5-benzoxazepine, 4,1-benzoxazepine, 3,1-benzoxazepine,1,5-benzothiazepine, 4,1-benzothiazepine, 3,1-benzothiazepine,1,5,1(H)-benzodiazepine, 1,4,1(H)-benzodiazepine and1,3,1(H)-benzodiazepine.

The 1,3-benzoxazole, 1,3-benzothiazole, 1,3,1(H)benzodiazole,1,4,2(H)-benzoxazine, 1,4,2(H)-benzothiazine, 1,4-benzodiazine,1,5-benzoxazepine, 1,5-benzothiazepine and 1,5,1(H)-benzodiazepineintermediate compounds may be prepared starting from a4-amino-2-methoxy-5-X-benzoic acid. A 4-acetylamino-3-amino-5-X-benzoicacid ester derivative is prepared by acidic esterification of thebenzoic acid with alcohol, preferably methanol. Protection of the aminegroup of the resulting ester, preferably by acetylation in a pyridinemedium, is followed by nitration, preferably with sulfuric acid andnitric acid, and reduction of the resulting nitro group to an aminogroup is effected by one of several known methods, such as shaking thereaction mixture with finely divided nickel or platinum under hydrogengas. A preferred X group for use in the foregoing reaction sequence ischloro.

The 1,3-benzoxazole, 1,4,2(H)-benzoxazine and 1,5-benzoxazepineintermediate compounds are prepared by transforming the unprotected3-amino group of the acetylamino benzoic acid ester derivative into ahydroxyl group, preferably by treatment with sulfuric acid and sodiumnitrite. The acetyl group is removed with base affording the4-amino-3-hydroxy benzoic acid ester compound.

The 1,3-benzothiazole, 1,4,2(H)-benzothiazine and 1,5-benzothiazepineintermediate compounds are prepared by transforming the unprotected3-amino group of the acetylamino benzoic acid ester derivative into asulfhydryl group, preferably by treatment with sulfuric acid, sodiumnitrite and sodium sulfide, affording the 4-acetylamino-3-sulfhydrylcompound. The acetyl group is removed with base affording the4-amino-3-sulfhydryl compound.

The 1,3,1(H)-benzodiazole, 1,4-benzodiazine and 1,5,1(H)-benzodiazepinecompounds are prepared by removing the protecting acetyl group from theacetylated benzoic acid intermediate, preferably by hydrolyzing theacetylamino group affording the 3,4-diamino intermediate compound.

The 4-amino-3-hydroxy, 4-amino-3-sulfhydryl and 3,4-diaminointermediates described above are used to prepare the compounds of thisinvention. Each intermediate is alkylated using a reagent such as adialkylating agent capable of reacting with the 3- and 4- hetero groupsof the intermediates to form benzoxazyl, benzothiazyl and benzodiazylbicyclic compounds. Cyclization may be effected with a compound of theformula X-CH₂ -(CH₂)_(d) -X, where each X is independently halo and d is0 to 2, or dibromomethane, or formaldehyde in the presence of dry acid,or phosgene, or chloroethylformate resulting in 5,6-, 6,6- or 7,6-benzobicyclic compounds. Preferred X groups are Cl and Br.

The 3,1,4(H)-benzoxazine, 3,1,4(H)-benzothiazine, 1,3-benzodiazine,4,1-benzoxazepine, 3,1-benzoxazepine, 4,1-benzothiazepine,3,1-benzothiazepine, 1,4,1(H)-benzodiazepine and 1,3,1(H)-benzodiazepineintermediate compounds may also be prepared starting from a4-amino-2-methoxy-5-X-benzoic acid which is esterified andamine-protected as described above.

The 3,1,4(H)-benzoxazine, 4,1-benzoxazepine and 3,1-benzoxazepineintermediate compounds are prepared by 3-hydroxyalkylation of theacetylamino benzoic acid ester derivative, preferably with sulfuric acidand either formaldehyde or acetaldehyde, affording the4-acetylamino-3-hydroxyalkyl intermediate compound.

The 3,1,4(H)-benzothiazine, 1,3-benzodiazine, 4,1-benzothiazepine,3,1-benzothiazepine, 1,4,1(H)-benzodiazepine and 1,3,1(H)-benzodiazepineintermediate compounds are prepared by functionalization of the metaposition of the 4-acetylamino-3-X-benzoic acid ester compound describedabove with an alkylene group, preferably a methylene group substitutedwith either hydroxy, halogen, amino or sulfhydryl. A preferred X groupin the ester starting material is halo and is most preferably chloro.The initial reaction involves the preparation of a hydroxymethyleneintermediate preferably using hydrochloric acid and either formaldehydeor acetaldehyde.

The 3,1,4(H)-benzothiazine, 4,1-benzothiazepine and 3,1-benzothiazepineintermediate compounds are prepared by transforming the hydroxyalkylgroup into a sulfhydrylalkyl group, preferably by treatment with NaSH.The 4-acetyl-amino-3-sulfhydrylalkyl intermediate compound results.

The 1,3-benzodiazine, 1,4,1(H)-benzodiazepine and1,3,1(H)-benzodiazepine intermediate compounds are prepared bytransforming the hydroxyalkyl group of the acetylamino benzoic acidester derivative into an aminoalkyl group, preferably by treatment withammonia affording the 4-acetylamino-3-aminoalkyl intermediate compound.

The amino-protecting acetyl group of the 4-acetylamino-3-hydroxyalkyl,4-acetylamino-3-sulfhydrylalkyl and 4-acetylamino-3-aminoalkylintermediates described above is removed with base, affording therespective 3-amino-4-hydroxyalkyl, 4-amino-3-sulfhydrylalkyl and3-amino-4-aminoalkyl intermediate compounds, respectively. Ring closureis effected by a reagent capable of reacting with the 3- and 4-heterogroups of the intermediates to form the appropriate 6,6 or 7,6 bicyclicintermediate compound. Preferred reagents include dibromomethane, or analdehyde in the presence of dry acid, such as formaldehyde oracetaldehyde in the presence of HCl gas.

The intermediates prepared as described above are used to prepare thecompounds within the scope of Formula I.

Compounds including various X substituents may be prepared by suitablechoice of starting material. Those substituents which require protectionmay be protected and deprotected as necessary or may be converted intothe desired substituent from an appropriate precursor group. Forexample, compounds where X is chloro, bromo or iodo, may be reacted withcuprous cyanide in quinoline at about 150° C. to produce compounds whereX is cyano. The cyano group may be converted to the acids, esters oramides.

The halo group may also be converted to the CF₃ group by reaction withtrifluoromethyliodide and copper powder at about 150° C. in DMF. Thehalo group may also be converted to the methylsulfonyl substituent byreaction with cuprous methanesulfinate in quinoline at 150° C.

When X is nitro, selective hydrogenation results in the correspondingamine, which may be mono- or di-alkylated with loweralkyl halides orsulfates. The amino group may also be diazotized to the diazoniumfluoride which is then thermally decomposed to the fluorine derivativecompound. The amine may also be diazotized and heated in an aqueousmedium to form the alcohol or heated in an alcohol to form the alkoxycompound. Chlorosulfonation of the amine group may form thecorresponding sulfamyl or mono- and di-alkylsulfamyl groups.

Depending on the chemistry involved in the synthesis, these reactionsmay be carried out at any appropriate stage of the synthesis. Forexample, the synthesis of X starting from NO₂ may be done after theclosed ring molecule or even after the carboxamide is prepared.

The compounds of this invention may contain at least one asymmetriccarbon atom and may have two centers when R₁ =R₂. As a result, thecompounds of Formula I may be obtained either as racemic mixtures or asindividual enantiomers. When two asymmetric centers are present theproduct may exist as a mixture of two diasteromers. The product may besynthesized as a mixture of the isomers and the desired isomer separatedby conventional techniques such as chromatography or fractionalcrystallization from which each diasteromer may be resolved. On theother hand, synthesis may be carried out by known sterospecificprocesses using the desired form of the intermediate which would resultin obtaining the desired specificity.

It is convenient to carry out condensation of the intermediatecarboxylic acids mentioned above with the amines of the formula H₂ N-Zusing the sterospecific materials. Accordingly, the acid may be resolvedinto its stereoisomers prior to condensation with resolved amine.

The compounds of this invention may be prepared by the followingrepresentative examples.

EXAMPLE 1 The Preparation of(N-1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-8-methoxy-3,4-dihydro-1,4,2(H)-benzoxazine-7-carboxamideStep 1. 4-Amino-2-methoxy-5-chlorobenzoate

HCl gas is bubbled through a mixture of4-Amino-2-methoxy-5-chlorobenzoic acid (22.0 g) in MeOH at 0° C. untilthe solid is completely dissolved. The solution is stirred at RT for 30minutes, evaporated and the resultant residue taken up in CH₂ Cl₂,evaporated and dried affording the desired compound which is used in thenext step without further purification.

Step 2. 4-N-Acetylamino-2-methoxy-5-chlorobenzoate

Acetyl chloride (21.6 g) is added dropwise to a 0° C. solution of themethyl ester of step 1 above (15.0 g) in pyridine (300 ml). The reactionmixture is stirred at RT for 2 hours, diluted with H₂ O, extracted withCH₂ Cl₂ (2×300 ml), washed with 5% HCl (4×250 ml), dried (Na₂ SO₄),filtered and evaporated to the desired product as a solid.

Step 3. 4-N-Acetylamino-2-methoxy-3-nitro-5-chlorobenzoate

The acetylamino compound of step 2 above (3.0 g) is added to a solutionof concentrated H₂ SO₄ (1 ml) in fuming HNO₃ (30 ml) cooled to -5° C.The reaction mixture is diluted with H₂ O, extracted with CH₂ Cl₂,washed with H₂ O, dried (Na₂ SO₄), filtered, evaporated andrecrystallized from hex/EtOAc to give the desired product as a solid.

Step 4. 4-N-Acetylamino-3-amino-2-methoxy-5-chlorobenzoate

The nitrobenzoate of step 3 above (2.0 g) is mixed with Raney nickel(2.0 g, water weight) in EtOAc (100 ml), shaken in a hydrogen atmosphereat 45 PSI for 1 hour, filtered through celite and evaporated to thedesired product as a white solid.

Step 5. 4-Amino-3-hydroxy-2-methoxy-5-chlorobenzoate

A solution of sodium nitrite (0.11 g) in H₂ O (1 ml) is added to asolution of the aminobenzoate of step 4 above (36 g) in 25% H₂ SO₄ (1ml) at 0° C., stirred for 10 minutes and diluted with a solution of H₂ O(10 ml) and urea (0.2 g). A hot solution of Na₂ SO₄ (15 g), H₂ O (10 ml)and concentrated H₂ SO₄ (10 ml) is added, the reaction mixture heated toreflux for one hour, cooled, and the resulting precipitate filtered,dried overnight and dissolved in excess MeOH. HCl gas is bubbled throughthis solution, which is evaporated affording a white solid which isdried and determined to be the desired compound by NMR.

Step 6. 4-Amino-3-chloroethoxy-2-methoxy-5-chlorobenzoate

4-Amino-3-hydroxy-2-methoxy-5-chlorobenzoate (10 g),1-bromo-2-chloroethane (22 ml) and potassium carbonate (0.61 g) aremixed under nitrogen gas in a solution of DMF (1 ml) and acetone (8 ml)and heated to reflux for 45 minutes. The solution is diluted with H₂ O,extracted with EtOAc, washed with H₂ O, dried (Na₂ SO₄), filtered, andevaporated to an oil. The oil is taken up in EtOH and heated to refluxovernight. The solution is worked up and chromatographed (1:1 Hex/Et)yielding the desired product.

Step 7.5-Chloro-8-methoxy-7-Methylcarboxy-3,4-dihydro-1,4,2(H)-benzoxazine

The chloroethyl ether of step 6 above (1.0 g) is purged with nitrogengas, heated in an oil bath at 220° C. for 15 minutes, cooled to 25° andpartitioned between ether (50 ml) and aqueous NaHCO₃ (50 ml, sat'd). Theether layer is removed, dried and evaporated and the residue ischromatographed on silica gel affording the desired product.

Step 8. 7-Carboxy-5-chloro-8-methoxy-3,4-dihydro-1,4,2(H)-benzoxazine

The benzoxazine of step 7 above (0.50 g) is dissolved in a solution ofMeOH (20 ml) and 10% NaOH (5 ml) and the reaction mixture is heated toreflux for 30 minutes. The alcohol is evaporated and the aqueous residueacidified with 10% HCl (15 ml) and extracted with CHCl₃ (3×30 ml). Thecombined layers are dried and evaporated to afford the desired product.

Step 9.(N-1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-8-methoxy-3,4-dihydro-1.4.2(H)benzoxazine-7-carboxamide

The carboxylic acid of step 8 above (2.0 mmoles) is dissolved in CHCl₃(10 ml), combined with Et₃ N (6.0 mmoles), cooled to -23° C. and mixedwith ethyl chloroformate (2.0 mmoles) for 30 minutes. Aminoquinuclidine(10 mmoles) and aqueous K₂ CO₃ (1 ml) are added and the reaction mixtureis stirred for 1 hour and diluted with H₂ O (10 ml). The organic layeris separated, washed with aqueous NaHCO₃ (50 ml, sat'd) and H₂ O (3×50ml), dried and evaporated affording the desired product.

EXAMPLE 2 The Preparation of(N-1-azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-methoxy-1,2,3,4-tetrahydro-1,4-benzodiazine-6-carboxamideStep 1. 3.4-Diamino-2-methoxy-5-chlorobenzoate

Sodium metal (1.51 g) in MeOH (20 ml) is added to a solution of4-N-acetylamino-3-amino-2-methoxy-5-chlorobenzoate in MeOH (20 ml) andthe reaction mixture is heated to reflux for 4 hours, poured into adilute acid/crushed ice bath, extracted with EtOAc, washed with aqueousNaCl (sat'd) and NaOH (10%), dried (Na₂ SO₄), filtered, evaporated andpurified on a column affording the desired product.

Step 6.8-Chloro-5-methoxy-6-methylcarboxy-2-keto-1,3,4-trihydro-1,4-benzodiazine

Bromo acetyl chloride (0.64 ml) is added dropwise to a 0° C. solution ofthe diaminobenzoate of step 5 above (1.8 g) and pyridine (1.8 ml) in CH₂Cl, (100 ml). The reaction mixture is stirred at RT for 45 minutes,washed with 5% aqueous HCl (3×100 ml) and aqueous NaCl (sat'd), dried(Na₂ SO₄), filtered and evaporated to a solid which is recrystallizedfrom hot toluene to give the desired product as a white solid.

Step 7. 6-Carboxy-8-chloro-5-methoxy-1,2,3,4-tetrahydro-1,4-benzodiazine

A 1M borane:THF solution (10.7 ml) is added to a solution of the diazinecompound of step 6 above (2.92 g) in THF (150 ml) at 0° C., and thereaction mixture is stirred at RT for 2 hours and cooled to 0° C.Additional borane:THF (10.7 ml) is added and the mixture is stirred atRT overnight. MeOH (3 ml) is added and the reaction mixture is stirredat RT for 15 minutes, evaporated, taken up in a 10% NaOH (6 ml)/MeOH (18ml) solution, heated to reflux under N, for 1 hour, poured into cold 5%aqueous HCl (200 ml), extracted with EtOAc (2×100 ml), washed with H₂ O,dried (Na₂ SO₄), filtered and evaporated to a white solid which NMRindicates is the desired product.

Step 8.(N-1-Azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-methoxy-1,2,3,4-tetrahydrobenzo-1,4-diazine-6-carboxamide

The carboxylic acid of step 7 above (3.71 mmoles) is dissolved in CHCl₃(10 ml), combined with Et₃ N (3.71 mmoles), cooled to -23° C. and mixedwith ethyl chloroformate (3.71 mmoles) for 30 minutes. Aminoquinuclidine(14.8 mmoles) and aqueous K₂ CO₃ (1 ml) are added and the reactionmixture is stirred for 1 hour and diluted with H₂ O (10 ml). The organiclayer is separated, washed with aqueous NaHCO₃ (50 ml, sat'd) and H₂ O(3×50 ml), dried, evaporated and chromatographed with Ether:MeOH (5 g,1:1) to give a brown oil which is dissolved in EtOH. Concentrated HCl isadded to the solution precipitating a white solid which is filtered andrecrystallized affording a white solid which NMR indicates is thedesired product.

The following compounds are prepared by procedures analogous to thosedescribed above.

(N-1-Azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-methoxy-3,4-dihydro-1,4,2(H)-benzothiazine-6-carboxamide,

(1-azabicyclo[3.3.1]non-4-yl)-5-chloro-8-methoxy-3,4-dihydro-1,4,2(H)-benzoxazine-7-carboxamide

(1-azabicyclo[3.3.1]non-4-yl)-5-chloro-8-methoxy-3,4-dihydro-1,4,2(H)-benzothiazine-7-carboxamide

(1-azabicyclo[3.3.1]non-4-yl)-6-chloro-9-methoxy-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carboxamide

(1-azabicyclo[3.3.1]non-4-yl)-6-chloro-9-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxamide

(1-azabicyclo[3.3.1]non-4-yl)-9-chloro-6-methoxy-2,3,4,5-tetrahydro-1,5,1(H)-benzodiazepine-7-carboxamide

(1-azabicyclo[3.3.1]non-4-yl)-9-chloro-6-methoxy-1-methyl-2,3,4-tetrhydro-1,5,1(H)-benzodiazepine-7-carboxamide

We have found that the compounds of this invention have gastricprokinetic, anti-emetic activity and lack D₂ receptor binding activityand as such possess therapeutic value in the treatment of upper bowelmotility and gastroesophageal reflux disorders. Further, the compoundsof this invention may be useful in the treatment of disorders related toimpaired gastrointestinal motility such as retarded gastric emptying,dyspepsia, flatulence, oesophageal reflux, peptic ulcer and emesis. Thecompounds of this invention exhibit 5-HT₃ antagonism and are consideredto be useful in the treatment of psychotic disorders such asschizophrenia and anxiety and in the prophylaxis treatment of migraineand cluster headaches. We have further found that these compounds areselective in that they have little or no dopaminergic antagonistactivity.

Various tests in animals can be carried out to show the ability of thecompounds of this invention to exhibit pharmacological responses thatcan be correlated with activity in humans. These tests involve suchfactors as the effect of the compounds of Formula I on gastric motility,emesis, selective antagonism of 5-HT₃ receptors and their D₂ dopaminereceptor binding properties.

It has been found that the compounds of this invention when tested inthe above variety of situations show a marked activity.

One such test is the "Rat Gastric Emptying: Amberlite Bead Method". Thistest is carried out as follows:

The study is designed to assess the effects of a test agent on gastricemptying of a solid meal in the rat. The procedure is a modification ofthose used in L. E. Borella and W. Lippmann (1980) Digestion 20: 26-49.

Procedure

Amberlite beads are placed in a phenol red solution and allowed to soakfor several hours. Phenol red serves as an indicator, changing the beadsfrom yellow to purple as their environment becomes more basic. Aftersoaking, the beads are rinsed with 0.1 NaOH to make them purple and thenwashed with deionized water to wash away the NaOH.

The beads are filtered several times through 1.18 and 1.4 mm sieves toobtain beads with diameters in between these sizes. This is done usinglarge quantities of deionized water. The beads are stored in salineuntil ready to use.

Male Sprague-Dawley rats are fasted 24 hours prior to the study withwater ad libitum. Rats are randomly divided in treatment groups with anN of 6 or 7.

Test agents are prepared in 0.5% methylcellulose and administered to therats orally in a 10 ml/kg dose volume. Control rats receive 0.5%methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60Amberlite beads intra-gastrically. The beads are delivered via a 3 inchpiece of PE 205 tubing attached to a 16 gauge tubing placed inside thetubing adapter to prevent the beads from being pulled back into thesyringe. The beads are flushed into each rat's stomach with 1 ml saline.

Rats are sacrificed 30 minutes after receiving the beads and theirstomachs are removed. The number of beads remaining in each stomach iscounted after rinsing the beads with NaOH.

The number of beads remaining in each stomach is subtracted from 60 toobtain the number of beads emptied. The mean number of beads ±S.E.M. isdetermined for each treatment group. The percent change from control iscalculated as follows: ##EQU1##

Statistical significance may be determined using a t-test forindependent samples with a probability of 0.05 or less considered to besignificant.

In order to demonstrate the ability of the compounds of this inventionas anti-emetic agents the following test for "Cisplatin-Induced Emesisin the Ferret" may be used. This test is a modified version of a paperreported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in CancerTreatment Reports: Vol. 66, No. 1. January 1982.

Cisplatin had been shown to cause emesis in the dog and cat. Florczyk,et al. have used the ferret to demonstrate the same effects.

Procedure

Male castrated, Fitch ferrets, weighing between 1.0 and 1.5 kg have anin Indwelling catheter placed in the jugular vein. After a 2-3 dayrecovery period, the experimental procedure is begun.

30 minutes prior to administration of Cisplatin, ferrets are dosed withthe compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg.

45 minutes after administration of Cisplatin, ferrets are again dosedwith 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.

Cisplatin is administered (i.v.) 30 minutes after the first dosing withthe 0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of2.0 ml/kg.

The time of Cisplatin administration is taken as time zero. Ferrets areobserved for the duration of the experiment (4 hours). The elapsed timeto the first emetic episode is noted and recorded, as are the totalnumber of periods of emesis.

An emetic (vomiting) episode is characterized by agitated behavior, suchas pacing around the cage and rapid to and fro movements. Concurrentwith this behavior are several retching movements in a row, followed bya single, large, retch which may or may not expulse gastric contents.

Immediately following the single large retch, the ferret relaxes. Singlecoughs or retches are not counted as vomiting episodes.

D-2 Dopamine Receptor Binding Assay

The D-2 dopamine receptor binding assay has been developed with slightmodifications using the method of Ian Cresse, Robert Schneider andSolomon H. Snyder, Europ. J. Pharmacol. 46: 377-381(1977). Spiroperidolis a butyrophenone neuroleptic whose affinity for dopamine receptors inbrain tissue is greater than that of any other known drug. It is ahighly specific D-1 dopamine (non-cyclase linked) receptor agent with K₁values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.

Sodium ions are important regulators of dopamine receptors. The affinityof the D-2 receptor is markedly enhanced by the presence of millimolarconcentrations of sodium chloride. The Kd in the absence and presence of120 mM sodium chloride is 1.2 and 0.086 nM respectively. Sodium chloride(120 mM) is included in all assays as a standard condition.

The caudate nucleum (corpus striatum) is used as the receptor sourcebecause it contained the highest density of dopamine receptors in thebrain and periphery.

Procedure

Male Charles-River rats weighing 250-300 g are decapitated and theirbrains removed, cooled on ice, and caudate dissected immediately andfrozen on dry ice. Tissue can be stored indefinitely at -70° C. Forassay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25° C.)using the polytron homogenizer. The homogenate is centrifuged at 40,000g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet isresuspended in fresh buffer and centrifuged again. The final pellet isresuspended in 150 volumes of assay buffer.

Specific ₁ H-spiroperidol binding is assayed in a total 2 ml reactionvolume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH7.4 at 35° C.), 5 mM MgSO., 2 mM EDTA 2NA, 120 mM NaCl, 0.1% ascorbicacid, 0.4 nM ₃ H-spiroperidol and test compound or assay buffer. Whencatecholamines are included in the assay, 10 μM pargyline should beincluded in the reaction mixture to inhibit monoamine oxidase. Samplesare incubated at 35° C. for 30 minutes followed by addition of 5 ml icecold 50 mM TRIS (pH 7.7 at 25° C.) and filtration through GF/B glassfiber filters on a Brandel Receptor Binding Filtration apparatus.Filters are washed twice with an additional 5 ml of tris buffer each.Assay groups are performed in triplicate and 1 μM D(+) butaclamol isused to determine nonspecific binding. Filters are placed in vialscontaining 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpmdetermined by liquid scintillation spectrophotometry using a quenchcurve. Proteins are determined by the method of Bradford, M. Anal.Biochem 72, 248(1976) using Bio-Rad's coomassie blue G-250 dye reagent.Bovine gamma Globulin supplied by BIO-RAD is used as the proteinstandard.

Bezold-Jarisch effect in anesthetized rats

Male rats 260-290 g are anesthetized with urethane 1.25 g/kg⁻¹ i.p., andthe trachea cannulated. The jugular vein is cannulated for intravenous(i.v.) injection of drugs. Blood pressure is recorded from a cannula inthe left carotid artery and connected to a heparin/saline-filledpressure transducer. Continuous heart rate measurements are taken fromthe blood pressure recordings. The Bezold-Jarisch effect is evoked byrapid, bolus i.v. injections of 5-HT and measurements are made of thefall in heart rate. In each rate, consistent responses are firstestablished with the minimum dose of 5-HT that evokes a clear fall inheart rate. Injections of 5-HT are given every 12 minutes and adose-response curve for the test compound is established by injectingincreasing doses of compound 5 minutes before each injection of 5-HT.The effect of the compound on the 5-HT-evoked bradycardia is calculatedas a percent of the bradycardia evoked by 5-HT before injection ofcompound.

In separate experiments to measure the duration of 5-HT antagonismcaused by the compounds of this invention, a single dose of compound isinjected 5 minutes before 5-HT, and the effects of 7 repeated challengeswith 5-HT are then monitored. The effects of the compound on theefferent vagal limb of the Bezold-Jarisch reflex are checked byelectrically stimulating the peripheral end of a cut vagus nerve.Unipolar electrical stimulation is applied every 5 minutes via a pair ofsilver electrodes, using I ms rectangular pulses in 5 strains with amaximally-effective voltage (20 V at 10 Hz). Pulse frequency may varyfrom 5-30 Hz and frequency-response curves are constructed before and 10minutes after i.v. injection of a single dose of compound.

The results of these above tests indicate that the compounds for thisinvention exhibit a valuable balance between the peripheral and centralaction of the nervous system and may be useful in the treatment ofdisorders related to impaired gastro-intestinal motility such as gastricemptying, dyspepsia, flatulence, esophageal reflux and peptic ulcer andin the treatment of disorders of the central nervous system such aspsychosis.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepithelially including transdermal, opthalmic, sublingual andbuccal; topically including ophthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 6% of the weightof the unit. The amount of active compound in such therapeuticallyuseful compositions is such that a suitable dosage will be obtained.Preferred compositions or preparations according to the presentinvention are prepared so that an oral dosage unit form contains betweenabout 50 and 300 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose of saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound sucroseas a sweetening agent, methyl and propylparabens as preservatives, a dyeand flavoring such as cherry or orange flavor. Of course, any materialused in preparing any dosage unit form should be pharmaceutically pureand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand formulations.

The active compound may also be administered parenterally orintraperiotoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimersal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions involves the incorporation of an agentdelaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administered alone toa mammal or in combination with pharmaceutically acceptable carriers, asnoted above, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and willvary with the form of administration and the particular compound chosen,and also, it will vary with the particular patient under treatment. Hewill generally wish to initiate treatment with small dosages by smallincrements until the optimum effect under the circumstances is reached.The therapeutic dosage will generally be from 0.1 to 20 mg or from about0.01 mg to about 5 mg/kg of body weight per day and higher although itmay be administered in several different dosage units from once toseveral times a day. Higher dosages are required for oraladministration.

We claim:
 1. A compound of the formula ##STR14## wherein: W is O, S orN-R₅ ;X is hydrogen, hydroxy, amino, mono- and di-loweralkylamino, halo,trifuoromethyl, sulfamyl, mono- and di-loweralkylsulfamyl orloweralkylsulfonyl; Y is loweralkyl, ##STR15## Z is ##STR16##3-quinuclidine, 4-quinuclidine, 4-(1-azabicylco[3.3.1]nonane),3-(9-methylazabicyclo[3.3.1]nonane),7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or4-[3-methoxy1-(3-[4-fluorophenoxy]propyl)piperidine]; R, R₁, R₂, R₃, R₄and R₅ are independently; vicinal R₂ groups may together form acarbocyclic ring; vicinal R₁ groups may form a double bond; vicinal Rand R₁ groups may form a double bond when m is 3; a and b are 1 to 3; mis 1 to 3; n is 0 to 2; m+n is 1 to 3; or a pharmaceutically acceptablesalt thereof.
 2. A compound of the formula ##STR17## where: W is O, S orN-R₅ ;X is hydrogen or halo; Y is methyl, ethyl, propyl, i-propyl,butyl, i-butyl, sec-butyl, t-butyl, pentyl, ##STR18## Z is3-quinuclidine, 4-quinuclidine, 4-(1-azabicyclo[3.3.1]-nonane),3-(9-methylazabicyclo[3.3.1]-nonane),7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine]; R, R₁, R₂ and R₅are independently hydrogen, methyl or ethyl; vicinal R₂ groups maytogether form a carbocyclic ring; vicinal R₁ groups may form a doublebond; a is 1 to 3; m is 1 or 2;or a pharmaceutically acceptable saltthereof.
 3. A compound of the formula ##STR19## where: W is oxygen ornitrogen;X is chloro or bromo; Z is 3-quinuclidine, 4-quinuclidine or4-(1-azabicyclo[3.3.1]-nonane); R is hydrogen or methyl; R₁ and R₂ areindependently hydrogen, methyl or ethyl; vicinal R₂ groups may togetherform a carbocyclic ring; vicinal R₁ groups may form a double bond; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 2 which is (N-1-1,4,2(H)-benzoxazine-7-carboxamide or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 2 which is(N-1-azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-methoxy-1,2,3,4-tetrahydro-1,4-benzodiazine-6-carboxamide or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 2 which is(1-azabicyclo[3.3.1]non-4-yl)-5-chloro-8-methoxy-3,4-dihydro-1,4,2(H)-benzoxazine-7-carboxamideor a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 2 which is(1-[3.3.1]non-4-yl)-6-chloro-9-methoxy-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carboxamideor a pharmaceutically acceptable salt thereof.